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Hodgkin Lymphoma

(Hodgkin’s Disease)

By

Peter Martin

, MD, Weill Cornell Medicine;


John P. Leonard

, MD, Weill Cornell Medicine

Reviewed/Revised Mar 2024
View PATIENT EDUCATION
Topic Resources

Hodgkin lymphoma is a localized or disseminated malignant proliferation of cells of the lymphoreticular system, primarily involving lymph node tissue, spleen, liver, and bone marrow. Symptoms typically include painless lymphadenopathy, sometimes with fever, night sweats, unintentional weight loss, pruritus, splenomegaly, and hepatomegaly. Diagnosis is based on lymph node biopsy. Treatment is curative in most cases and consists of chemotherapy with or without other treatment modalities, including antibody-drug conjugates, immunotherapy, and radiation therapy.

In the United States, it is estimated that in 2023 about 8,830 new cases of Hodgkin lymphoma will have been diagnosed, and about 900 people will have died of the disease (1 General reference Hodgkin lymphoma is a localized or disseminated malignant proliferation of cells of the lymphoreticular system, primarily involving lymph node tissue, spleen, liver, and bone marrow. Symptoms... read more General reference ). The male:female ratio is about 1.2:1. Hodgkin lymphoma is rare before age 10 years and is most common between ages 15 and 40 years; a second peak occurs in people > 60 years.

General reference

Pathophysiology of Hodgkin Lymphoma

Hodgkin lymphoma results from the clonal transformation of cells of B-cell origin, giving rise to pathognomic binucleated Reed-Sternberg cells.

Most patients also develop a slowly progressive defect in cell-mediated immunity (T-cell function) that, in advanced disease, contributes to common bacterial and unusual fungal, viral, and protozoal infections. Humoral immunity (antibody production) is depressed in advanced disease. Death can result from infection or progressive disease.

Symptoms and Signs of Hodgkin Lymphoma

Most patients with Hodgkin lymphoma present with painless cervical adenopathy. Although the mechanism is unclear, pain rarely may occur in diseased areas immediately after drinking alcoholic beverages, sometimes providing an early indication of the diagnosis.

Other manifestations develop as the disease spreads through the reticuloendothelial system, generally to contiguous sites. Intense pruritus refractory to usual therapies may occur early.

Systemic symptoms include fever, night sweats, and loss of appetite resulting in unintentional weight loss (> 10% of body weight in previous 6 months), which are referred to as "B symptoms." B symptoms are significant to prognosis and staging because they may signify involvement of internal lymph nodes (mediastinal or retroperitoneal), viscera (liver), or bone marrow. Splenomegaly is often present; hepatomegaly is unusual. Pel-Ebstein fever (a few days of high fever regularly alternating with a few days to several weeks of normal or below-normal temperature) occasionally occurs. Cachexia is common as disease advances.

Bone involvement is often asymptomatic but may cause vertebral osteoblastic lesions (ivory vertebrae) and, rarely, pain with osteolytic lesions and compression fractures.

Intracranial, gastric, and cutaneous lesions are rare and, when present, can suggest uncontrolled HIV-associated Hodgkin lymphoma.

Local compression by tumor masses often causes symptoms and signs, including

Epidural invasion that compresses the spinal cord may result in paraplegia.

Horner syndrome and laryngeal paralysis may result when enlarged lymph nodes compress the cervical sympathetic and recurrent laryngeal nerves.

Neuralgic pain follows nerve root compression.

Diagnosis of Hodgkin Lymphoma

  • Lymph node biopsy

  • FDG-PET/CT of chest, abdomen, and pelvis for staging

  • MRI if neurologic symptoms are present

Hodgkin lymphoma is usually suspected in patients with painless lymphadenopathy or mediastinal adenopathy detected on physical examination or routine chest x-ray (1 Diagnosis references Hodgkin lymphoma is a localized or disseminated malignant proliferation of cells of the lymphoreticular system, primarily involving lymph node tissue, spleen, liver, and bone marrow. Symptoms... read more Diagnosis references ).

Similar lymphadenopathy can result from viral infections such as infectious mononucleosis Infectious Mononucleosis Infectious mononucleosis is caused by Epstein-Barr virus (EBV, human herpesvirus type 4) and is characterized by fatigue, fever, pharyngitis, and lymphadenopathy. Fatigue may persist weeks or... read more Infectious Mononucleosis (EBV) or cytomegalovirus (CMV) infection Cytomegalovirus (CMV) Infection Cytomegalovirus (CMV, human herpesvirus type 5) can cause infections that have a wide range of severity. A syndrome of infectious mononucleosis that lacks severe pharyngitis is common. Severe... read more , toxoplasmosis Toxoplasmosis Toxoplasmosis is infection with Toxoplasma gondii. Symptoms range from none to benign lymphadenopathy, a mononucleosis-like illness, to life-threatening central nervous system (CNS) disease... read more Toxoplasmosis , non-Hodgkin lymphoma Non-Hodgkin Lymphomas Non-Hodgkin lymphomas are a heterogeneous group of disorders involving malignant, monoclonal proliferation of lymphoid cells in lymphoreticular sites, including lymph nodes, bone marrow, the... read more Non-Hodgkin Lymphomas , or leukemia Overview of Leukemia Leukemia is a malignant condition involving the excess production of immature or abnormal leukocytes, which eventually suppresses the production of normal blood cells and results in symptoms... read more . Similar findings on chest radiograph can result from lung cancer Lung Carcinoma Lung carcinoma is the leading cause of cancer-related death in men and women worldwide. About 85% of cases are related to cigarette smoking. Symptoms can include cough, chest discomfort or pain... read more Lung Carcinoma , sarcoidosis Sarcoidosis Sarcoidosis is an inflammatory disorder resulting in noncaseating granulomas in one or more organs and tissues; etiology is unknown. The lungs and lymphatic system are most often affected, but... read more Sarcoidosis , or tuberculosis Tuberculosis (TB) Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more Tuberculosis (TB) .

Chest radiograph or physical examination abnormalities should be confirmed with CT or positron emission tomography (PET) scan of the chest in order to choose the most efficient biopsy procedure. If only mediastinal nodes are enlarged, mediastinoscopy Mediastinoscopy and Mediastinotomy Mediastinoscopy is a procedure in which an endoscope is introduced through the suprasternal notch into the mediastinum to allow visualization of it. Mediastinotomy is surgical opening of the... read more , video-assisted thoracoscopy Thoracoscopy and Video-Assisted Thoracoscopic Surgery Thoracoscopy is a procedure in which an endoscope is introduced to visualize the pleural space. Thoracoscopy can be used for visualization (pleuroscopy) or for surgical procedures. Surgical... read more (VATS), or a Chamberlain procedure (a limited left anterior thoracostomy allowing biopsy of mediastinal lymph nodes inaccessible by cervical mediastinoscopy) may be indicated. CT-guided core needle biopsy may also be considered; fine-needle aspiration is often inadequate for the diagnosis of Hodgkin lymphoma.

Biopsy reveals Reed-Sternberg cells (large, binucleated cells) in a characteristically heterogeneous cellular infiltrate, consisting of histiocytes, lymphocytes, monocytes, plasma cells, and eosinophils. Classic Hodgkin lymphoma has 4 histopathologic subtypes (2 Diagnosis references Hodgkin lymphoma is a localized or disseminated malignant proliferation of cells of the lymphoreticular system, primarily involving lymph node tissue, spleen, liver, and bone marrow. Symptoms... read more Diagnosis references ) (see table ):

  • Nodular sclerosis: Dense fibrous tissue surrounding nodules of Hodgkin tissue

  • Mixed cellularity: A moderate number of Reed-Sternberg cells with a mixed background infiltrate

  • Lymphocyte-rich: Few Reed-Sternberg cells but many B cells

  • Lymphocyte-depleted: Numerous Reed-Sternberg cells plus extensive fibrosis

Nodular lymphocyte-predominant Hodgkin lymphoma has been reclassified as a non-Hodgkin B-cell lymphoma by the International Consensus Classification and is called nodular lymphocyte predominant B-cell lymphoma (3 Diagnosis references Hodgkin lymphoma is a localized or disseminated malignant proliferation of cells of the lymphoreticular system, primarily involving lymph node tissue, spleen, liver, and bone marrow. Symptoms... read more Diagnosis references ).

Complete blood count (CBC) with differential, erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), and kidney function and liver tests are generally done. Test results may be abnormal but are nondiagnostic.

CBC may show a slight polymorphonuclear leukocytosis. Lymphocytopenia may occur early and is an adverse prognostic factor. Eosinophilia is common, and thrombocytosis also may be present. Anemia, often microcytic, usually develops with advanced disease. In advanced anemia, defective iron reutilization is characterized by a low serum iron level, low iron-binding capacity, an elevated serum ferritin level, and an increased bone marrow iron level. Pancytopenia is occasionally caused by bone marrow invasion, more commonly in the lymphocyte-depleted subtype.

Elevated serum alkaline phosphatase levels may be present, but elevations do not always indicate bone marrow or liver involvement. Increases in leukocyte alkaline phosphatase, serum haptoglobin, and other acute-phase reactants usually reflect the presence of inflammatory cytokines due to active Hodgkin lymphoma. These substances are measured and tests are sometimes done to evaluate nonspecific symptoms, and results can suggest Hodgkin lymphoma; they are not done on all lymphoma patients. Erythrocyte sedimentation rate (ESR), an indirect marker of inflammation, is commonly ordered and elevation predicts a less favorable outcome.

A combined fluorodeoxyglucose (FDG)-PET/CT scan of the chest, abdomen, and pelvis is the imaging study of choice for staging Hodgkin lymphoma (see below Staging Hodgkin lymphoma is a localized or disseminated malignant proliferation of cells of the lymphoreticular system, primarily involving lymph node tissue, spleen, liver, and bone marrow. Symptoms... read more Staging ). Bone lesions are detected more commonly with the use of FDG-PET imaging. If combined FDG-PET/CT is not available, a contrast-enhanced CT scan of the chest, abdomen, and pelvis is done.

A bone marrow biopsy is usually only done if a PET/CT scan is not obtained and if the findings might alter management.

Other tests are done depending on findings (eg, MRI for symptoms of cord compression). Other recommended tests include the cardiac ejection fraction if the use of anthracyclines is anticipated and pulmonary function tests if the use of bleomycin is being considered.

Table

Staging

After diagnosis, stage is determined to guide therapy. The commonly used Lugano staging system (see table ) incorporates

Laparotomy is not required for staging.

Table

Diagnosis references

  • 1. Cheson BD, Fisher RI, Barrington SF, et al: Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: The Lugano classification. J Clin Oncol 32(27):3059–3068, 2014.

  • 2. Alaggio R, Amador C, Anagnostopoulos I, et al: The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms [published correction appears in Leukemia 2023 Sep;37(9):1944-1951]. Leukemia 36(7):1720–1748, 2023. doi:10.1038/s41375-022-01620-2

  • 3. Campo E, Jaffe ES, Cook JR, et al. The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee [published correction appears in Blood 2023 Jan 26;141(4):437]. Blood 2022;140(11):1229-1253. doi:10.1182/blood.2022015851

Treatment of Hodgkin Lymphoma

  • Chemotherapy

  • Antibody-drug conjugate (eg, brentuximab vedotin)

  • Immunotherapy (eg, immune checkpoint inhibitors)

  • Radiation therapy

  • Sometimes autologous stem cell transplantation

The choice of treatment modality is complex and depends on the precise stage of disease. Before treatment and when applicable, patients should discuss options to preserve fertility with their oncologists and a fertility specialist.

Initial treatment

Limited-stage disease is generally treated with an abbreviated chemotherapy regimen of doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) with or without radiation therapy Radiation Therapy for Cancer Radiation therapy can cure many cancers (see also Overview of Cancer Therapy), particularly those that are localized or that can be completely encompassed within a radiation field. Radiation... read more . In patients with bulky mediastinal disease, chemotherapy may be of longer duration or of a different type, and radiation therapy is often included. Bleomycin is generally avoided in patients >60 years due to increased risk of pulmonary toxicity.

Advanced-stage disease is generally managed with regimens based on the AVD backbone. Reasonable options may include ABVD, AVD (no bleomycin), BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), AVD plus brentuximab vedotin, and AVD plus nivolumab, which is poised to become the new standard of care. The choice of therapy in advanced-staged disease is individualized and based on patient characteristics (eg, disease stage, comorbidities), potential medication toxicities, and patient preference. These alternative approaches are largely based on the findings of large randomized trials. In the RATHL (Response-Adapted Therapy in Advanced Hodgkin Lymphoma) trial, patients were treated with ABVD, and those who had a negative PET scan after 2 cycles received 4 additional cycles with AVD (no bleomycin), while those who had a positive PET scan were escalated to BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone [ 1 Treatment references Hodgkin lymphoma is a localized or disseminated malignant proliferation of cells of the lymphoreticular system, primarily involving lymph node tissue, spleen, liver, and bone marrow. Symptoms... read more Treatment references ]). In the ECHELON-1 trial, patients treated with AVD plus the anti-CD30 antibody-drug conjugate brentuximab vedotin had superior outcomes to patients treated with ABVD, with higher-risk younger patients appearing to benefit more (2, 3 Treatment references Hodgkin lymphoma is a localized or disseminated malignant proliferation of cells of the lymphoreticular system, primarily involving lymph node tissue, spleen, liver, and bone marrow. Symptoms... read more Treatment references ). Optimal management of very old or frail patients is not standardized.

Subsequent treatment

Multiple second-line chemotherapy regimens are considered acceptable for patients who are not cured with first-line therapy. For patients who achieve a good response to second-line therapy, high-dose chemotherapy and autologous stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more should be considered, while non-responders may be candidates for subsequent lines of therapy or allogeneic stem cell transplantation.

Brentuximab vedotin and the checkpoint inhibitors nivolumab and pembrolizumab can be used for treatment of patients with Hodgkin lymphoma who have received at least 2 prior forms of therapy (4, 5 Treatment references Hodgkin lymphoma is a localized or disseminated malignant proliferation of cells of the lymphoreticular system, primarily involving lymph node tissue, spleen, liver, and bone marrow. Symptoms... read more Treatment references ).

Complications of treatment

Chemotherapy, particularly with drugs such as the alkylating agents (mechlorethamine, cyclophosphamide, procarbazine), doxorubicin, and etoposide, increase the risk of leukemia between years 3 and 10 post-therapy.

Radiation therapy carries increased risk of malignant solid tumors (eg, breast, gastrointestinal, lung, thyroid, soft tissue).

Bleomycin can induce lung injury, which can be severe and rarely fatal.

Brentuximab vedotin is myelosuppressive and, especially when combined with vinblastine, can result in durable peripheral neuropathy.

Immune checkpoint inhibitors are associated with immune-related toxicities.

Posttreatment surveillance

All patients who are not PET-negative at the end of induction therapy should have a biopsy or be followed closely with serial imaging; if residual disease is present, additional treatment is necessary. Once in remission, patients should be followed for signs and symptoms of relapse for 5 years. Those with manifestations of relapse, defined as reappearance of disease at sites of prior disease or at new sites, should have imaging with PET/CT or CT alone. Routine, scheduled imaging in asymptomatic patients is not mandatory. For a schedule of posttreatment surveillance, see table .

Table

Treatment references

  • 1. Johnson P, Federico M, Kirkwood A, et al: Adapted treatment guided by interim PET-CT scan in advanced Hodgkin's lymphoma. N Engl J Med 374(25):2419– 2429, 2016.

  • 2. Connors JM, Jurczak W, Straus DJ, et al: Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin's lymphoma. N Engl J Med 378(4):331–344, 2018. Epub 2017 Dec 10.

  • 3. Straus DJ, Długosz-Danecka M, Connors JM, et al: Brentuximab vedotin with chemotherapy for stage III or IV classical Hodgkin lymphoma (ECHELON-1): 5-year update of an international, open-label, randomised, phase 3 trial. Lancet Haematol 8(6):e410–e421, 2021. doi: 10.1016/S2352-3026(21)00102-2

  • 4. Armand P, Engert A, Younes A, et al: Nivolumab for Relapsed/Refractory Classic Hodgkin Lymphoma After Failure of Autologous Hematopoietic Cell Transplantation: Extended Follow-Up of the Multicohort Single-Arm Phase II CheckMate 205 Trial [published correction appears in J Clin Oncol 2018 Sep 10;36(26):2748]. J Clin Oncol 36(14):1428–1439, 2018. doi:10.1200/JCO.2017.76.0793

  • 5. Chen R, Zinzani PL, Fanale MA, et al: Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma. J Clin Oncol 35(19):2125–2132, 2017. doi:10.1200/JCO.2016.72.1316

Prognosis for Hodgkin Lymphoma

About 85 to 90% of patients with limited-stage classic Hodgkin lymphoma are cured compared with 75 to 80% of patients with advanced-stage disease (1 Prognosis reference Hodgkin lymphoma is a localized or disseminated malignant proliferation of cells of the lymphoreticular system, primarily involving lymph node tissue, spleen, liver, and bone marrow. Symptoms... read more Prognosis reference ). Limited-stage disease is frequently subdivided into favorable and unfavorable prognostic groups. Unfavorable disease is based on risk factors, for example:

  • Presence of bulky disease

  • 4 nodal sites involved

  • Age > 50 years

  • Erythrocyte sedimentation rate (ESR) > 50 mm/hour with no B symptoms or > 30 mm/hour with B symptoms (weight loss, fever, night sweats)

Risk factors in advanced-stage Hodgkin lymphoma include

  • Male sex

  • Age > 45 years

  • Stage 4 disease

  • Signs of tumor-induced inflammation (low albumin, anemia, leukocytosis, and lymphopenia)

However, selection of which risk factors to use in estimating prognosis is still subject to revision. Patients who do not achieve complete remission with treatment, or who relapse within 12 months have a poor prognosis.

Prognosis reference

  • 1. National Institutes of Health: National Cancer Institute Surveillance, Epidemiology, and End-Results (SEER) Program. Cancer Stat Facts—Hodgkin Lymphoma. SEER 2023

Key Points

  • Hodgkin lymphoma is of B cell origin.

  • Patients usually present with painless lymphadenopathy or with incidental cervical or mediastinal adenopathy discovered on chest radiograph or physical examination.

  • Biopsy shows pathognomonic, binucleated Reed-Sternberg cells.

  • Most patients are cured using combination chemotherapy and sometimes additional systemic therapies or radiation therapy.

  • Subsequent therapeutic options include high-dose chemotherapy, autologous stem cell transplantation, or brentuximab vedotin and the checkpoint inhibitors nivolumab and pembrolizumab.

More Information

The following English language resource provides information for clinicians and support and information for patients. THE MANUAL is not responsible for the content of this resource.

Drugs Mentioned In This Article

Drug Name Select Trade
Dilantin, Dilantin Infatabs, Dilantin-125, Phenytek
Blenoxane
ADCETRIS
Adriamycin, Adriamycin PFS, Adriamycin RDF, Rubex
Velban
DTIC-Dome
Etopophos, Toposar, VePesid
Cyclophosphamide, Cytoxan, Neosar
Oncovin, Vincasar PFS
Matulane
Deltasone, Predone, RAYOS, Sterapred, Sterapred DS
Opdivo
Keytruda
Mustargen, VALCHLOR
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